Unresolved questions regarding cellular cysteine sources and their possible relationships to ferroptosis
Cysteine is essential for the synthesis of glutathione (GSH), coenzyme A, various sulfur-containing metabolites, and most proteins. In many cells, cysteine is derived from extracellular disulfide sources such as cystine, glutathione disulfide, and peptides. Enzymatic systems driven by thioredoxin reductase-1 (TrxR1) or glutathione-disulfide reductase (GSR) facilitate the reduction of cystine through thioredoxins, glutaredoxins, or other thioredoxin-fold proteins. Free cystine enters cells via the cystine-glutamate antiporter, xCT, though plasma glutathione-disulfide may also serve as a significant cystine source systemically. Erastin, which inhibits both xCT and voltage-dependent anion channels, induces ferroptotic cell death—a process that can be counteracted by iron chelators. Many cancer cells are particularly prone to ferroptosis, a form of cell death that has been proposed as a potential therapeutic target. Ferroptosis is associated with lipid peroxidation and a loss of either glutathione peroxidase-4 (GPX4) or ferroptosis suppressor protein-1 (FSP1), both of which prevent the accumulation of lipid peroxides. It has been suggested that inhibition of xCT leads to cellular cysteine deficiency, lowering GSH levels, which in turn depletes the reducing power needed by GPX4, allowing lipid peroxides to accumulate and triggering ferroptosis. However, aspects of ferroptosis remain unclear and require further investigation. For example, neither disruption of GSH synthesis, depletion of GSH, nor inhibition of glutathione-disulfide reductase (GSR) induces ferroptosis in animal models. In this study, we reevaluate the relationships between Erastin, xCT, GPX4, cellular cysteine and GSH, as well as compounds like RSL3 or ML162, in relation to ferroptosis. We conclude that while both cysteine and ferroptosis represent potential vulnerabilities in cancer, the exact relationship between them remains insufficiently understood.